Indole derivatives and their use as medicament

ABSTRACT

The invention relates to novel indole derivatives of the general formula 1, to their preparation and to their use as medicaments, in particular for treating tumors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. application Ser.No. 09/910,140, filed on Jul. 20, 2001, the content of which is herebyincorporated by reference herein in its entirety.

The invention relates to novel indole derivatives of the general formula1, to their preparation and to their use as medicaments, in particularfor treating tumors.

Indol-3-yl derivatives having certain 2-, 3-, 4- and 8-quinolineradicals are described in the German application DE 198 14 838.0.However, indol-3-yl derivatives having 5-, 6- or 7-quinolinesubstituents are neither described nor suggested in this publication.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows in vitro cytotoxicity of D-69429 in tumor cell ines foreight (8) substance concentrations.

DETAILED DESCRIPTION

According to one aspect of the invention, novel indole derivatives ofthe general formula 1

in which

-   R denotes hydrogen; straight-chain or branched (C₁-C₆)-alkyl;    (C₁-C₆)-alkyl which is mono- or polysubstituted by aryl, where the    aryl radical [lacuna] unsubstituted or mono- to penta-[lacuna] by    identical or different substituents from the group consisting of    halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, carboxyl,    (C₁-C₆)-alkoxycarbonyl, preferably tert-butoxycarbonyl,    straight-chain or branched (C₁-C₆)-alkyl, which is substituted by    one or more fluorine atoms, preferably trifluoromethyl, hydroxyl,    straight-chain or branched (C₁-C₆)-alkoxy, preferably methoxy or    ethoxy; benzyloxy or aryl-(C₁-C₆)-alkyl, where the aryl radical may    be unsubstituted or mono- or pentasubstituted by identical or    different substituents from the group consisting of (C₁-C₆)-alkyl,    halogen and straight-chain or branched (C₁-C₆)-alkyl which is    substituted by one or more fluorine atoms, preferably    trifluoromethyl; straight-chain or branched    (C₁-C₆)-alkoxy-(C₁-C₅)-alkyl [sic], substituted or unsubstituted    aryl-(C₁-C₆)-alkyloxycarbonyl, preferably benzyloxycarbonyl,    straight-chain or branched (C₁-C₆)-alkyloxycarbonyl, straight-chain    or branched (C₁-C₆)-alkylcarbonyl, preferably acetyl,    (C₂-C₆)-alkenyl, preferably allyl, (C₂-C₆)-alkynyl, preferably    ethynyl or propargyl, or straight-chain or branched    cyano-(C₁-C₆)-alkyl, preferably cyanomethyl;-   R₁ denotes a saturated, unsaturated or aromatic (C2-C14)-heterocycle    which contains one or more heteroatoms selected from the group    consisting of N, O and S and which may be attached to the amide    nitrogen directly or via a (C1-C6)-alkyl bridge, where the    (C₁-C₄)-alkyl radical may be unsubstituted or mono-[lacuna]    polysubstituted by identical or different substituents from the    group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2-,    4-, 5- or 6-pyrimidinyl radical may in each case be unsubstituted or    mono- to trisubstituted by identical or different substituents from    the group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,    amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,    (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,    (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or    polysubstituted by fluorine, preferably trifluoromethyl,    (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl, with the proviso that    R1 does not represent unsubstituted 2- or 4-pyrimidinyl or a    2-pyrimidinyl radical which is mono- or polysubstituted by methyl;    and except for (C1-C6)-alkyl-, halogen-, nitro-, amino- and    (C1-C6)-alkylamino-substituted or unsubstituted 2-, 3-, 4- and    8-quinolyl and 2-, 3- and 4-quinolylmethyl in which the ring carbon    atoms of the pyridylmethyl moiety are unsubstituted or substituted    by (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, amino and    (C1-C6)-alkoxycarbonylamino;-   R₂ denotes hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl which is mono- or    polysubstituted by halogen, (C₁-C₆)-alkyl which is mono- or    polysubstituted by phenyl, where the phenyl radical may be    unsubstituted or mono- to pentasubstituted by identical or different    substituents from the group consisting of halogen, preferably    chlorine, bromine or iodine, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,    carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkyl which is mono- or    polysubstituted by halogen, preferably trifluoromethyl, hydroxyl,    (C₁-C₆)-alkoxy, preferably methoxy or ethoxy, phenyl-(C₁-C₆)-alkoxy,    preferably benzyloxy, nitro, amino, mono-(C₁-C₆)-alkylamino,    di-(C₁-C₆)-alkylamino, mono-(C₃₋₆)-cycloalkylamino,    di-(C₃₋₆)-cycloalkylamino, (C₁-C₆)-acylamino,    phenyl-(C₁-C₆)-alkylamino, arylcarbonylamino,    heteroarylcarbonylamino, (C₁-C₆)-alkylsulfonamido, arylsulfonamido,    maleinimido, succinimido, phthalimido, benzyloxycarbonylamino    (Z-amino), tert-butoxycarbonylamino (BOC-amino),    9-fluorenylmethoxycarbonylamino (Fmoc-amino), triphenylmethylamino    (Tr-amino), 2-(4′-pyridyl)-ethoxycarbonylamino (Pyoc-amino),    diphenylmethylsilylamino (DPMS-amino), by —NH—CH₂—COOH;    —NH—CH(CH₃)—COOH; (CH₃)₂CH—CH₂—CH₂—CH(NH—)—COOH;    H₃C—CH₂—CH(CH₃)—CH(NH—)—COOH;    -   HOH₂C—CH(NH—)—COOH; phenyl-CH₂—CH(NH—)—COOH;        (4-imidazolyl)-CH₂—CH(NH—)—COOH;        HN═C(NH₂)—NH—(CH₂)₃—CH(NH—)—COOH; H₂N—(CH₂)₄—CH(NH—)—COOH;    -   H₂N—CO—CH₂—CH(NH—)—COOH; HOOC—(CH₂)₂—CH(NH—)—COOH;    -   a 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolyl-(C₁-C₆)-alkyl radical,        where the 2-, 3-, 4-, 5-, [sic] 6-, 7- and 8-quinolyl radical        may be unsubstituted or mono- to hexasubstituted by identical or        different substituents from the group consisting of halogen,        (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy;    -   a 2-, 3- and 4-pyridyl-(C₁-C₆)-alkyl radical, where the 2-, 3-        and 4-pyridyl radical may be unsubstituted or mono- to        tetrasubstituted by identical or different substituents from the        group consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkoxy;    -   an arylcarbonyl radical, where the aryl radical may be        unsubstituted or mono- to pentasubstituted by identical or        different substituents from the group consisting of halogen,        (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, carboxyl, cyano,        (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine atoms preferably trifluoromethyl,        hydroxyl, (C₁-C₄)-alkoxy preferably methoxy or ethoxy,        aryl-(C₁-C₄)-alkoxy, preferably benzyloxy;-   R₃ and R₄ may be attached to the indole carbon atoms C-2, C-4, C-5,    C-6 or C-7 and independently of one another denote hydrogen,    hydroxyl, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₆)-alkylcarbonyl,    (C₁-C₆)-alkoxy, halogen, aryl-(C₁-C₄)-alkoxy, preferably benzyloxy,    nitro, amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,    (C₁-C₆)-alkoxycarbonylamino,    (C₁-C₆)-alkoxycarbonylamino-(C₁-C₆)-alkyl, cyano, straight-chain or    branched cyano-(C₁-C₆)-alkyl, carboxyl, (C₁-C₄)-alkoxycarbonyl,    (C₁-C₄)-alkyl which is substituted by one or more fluorine atoms,    preferably trifluoromethyl group, carboxy-(C₁-C₆)-alkyl or    (C₁-C₆)-alkoxycarbonyl-(C₁-C₆)-alkyl;-   Z₁ denotes oxygen or sulfur or geminally attached hydrogen and    hydroxyl;-   Z₂ denotes oxygen or sulfur,    -   their tautomers, stereoisomers, including the diastereomers and        enantiomers, and the physiologically acceptable salts thereof,        are provided.

Thus, for example, the compounds of the general formula (1) according tothe invention which have one or more centers of chirality and which arepresent as racemates can be separated by methods known per se into theiroptical isomers, i.e. enantiomers or diastereomers. The separation canbe carried out by column separation on chiral phases or byrecrystallization from an optically active solvent or using an opticallyactive acid or base or by derivatization with an optically activereagent, such as, for example, an optically active alcohol, andsubsequent removal of the radical.

Furthermore, the indole derivatives of the formula (1) according to theinvention can be converted into their salts with inorganic or organicacids, in particular, for pharmaceutical use, into their physiologicallyacceptable salts. Acids which are suitable for this purpose are, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, fumaric acid, succinic acid, lactic acid, malic acid, embonicacid, malonic acid, citric acid, acetic acid, tartaric acid,trifluoroacetic acid, methanesulfonic acid, sulfoacetic acid or maleicacid.

Moreover, the compounds of the formula (1) according to the inventioncan, if they contain a sufficiently acidic group, such as a carboxylgroup, be converted, if desired, into their salts with inorganic ororganic bases, in particular, for pharmaceutical use, into theirphysiologically acceptable salts. Bases which are suitable for thispurpose are, for example, sodium hydroxide, potassium hydroxide, calciumhydroxide, lysine, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

According to a preferred embodiment, indole derivatives of the generalformula (1) above are provided in which R, R2, R3, R4, Z1 and Z2 havethe meanings given above and

-   R1 denotes a 2-, 4-, 5- or 6-pyrimidinyl radical or 2-, 4-, 5- or    6-pyrimidinyl-(C₁-C₄)-alkyl radical, where the (C₁-C₄)-alkyl radical    may be unsubstituted or mono-[lacuna] polysubstituted by identical    or different substituents from the group consisting of    (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2-, 4-, 5- or    6-pyrimidinyl radical may be unsubstituted or mono- to    trisubstituted by identical or different substituents from the group    consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro, amino,    mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,    (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,    (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or    polysubstituted by fluorine, preferably trifluoromethyl,    (C₆-C₁₀)-aryl, or (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl, with the proviso that    R1 does not represent unsubstituted 2- or 4-pyrimidinyl or a    2-pyrimidinyl radical which is mono- or polysubstituted by methyl;    -   a 3-, 4-, 5- or 6-pyridazinyl radical or 3-, 4-, 5- or        6-pyridazinyl-(C₁-C₄)-alkyl radical, where the (C₁-C₄)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 3-, 4-, 5- or        6-pyridazinyl radical may be unsubstituted or mono- to        trisubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 3-, 5- or 6-pyrazinyl radical or 2-, 3-, 5, -[sic] or        6-pyrazinyl-(C₁-C₄)-alkyl radical, where the (C₁-C₄)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2-, 3-, 5, -[sic] or        6-pyrazinyl radical may be unsubstituted or mono- to        trisubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl radical or 3-, 4-, 5-, 6-,        7-, or 8-cinnolinyl-(C₁-C₄)-alkyl radical, where the        (C₁-C₄)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl radical may be unsubstituted        or mono- to pentasubstituted by identical or different        substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl radical or 2-, 4-, 5-,        6-, 7- or 8-quinazolinyl-(C₁-C₄)-alkyl radical, where the        (C₁-C₄)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen and oxo        (═O) and the or [sic] 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl        radical may be unsubstituted or mono- to pentasubstituted by        identical or different substituents from the group consisting of        hydrogen, (C₁-C₆)-alkyl, halogen, nitro, amino,        mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl radical or 2-, 3-, 5-,        6-, 7- or 8-quinoxalinyl-(C₁-C₄)-alkyl radical, where the        (C₁-C₄)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        or [sic] 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl radical may be        unsubstituted or mono- to pentasubstituted by identical or        different substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl radical or 1-, 4-, 5-,        6-, 7- or 8-phthalazinyl-(C₁-C₄)-alkyl radical, where the        (C₁-C₄)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        or [sic] 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl radical may be        unsubstituted or mono- to pentasubstituted by identical or        different substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl radical or 2-, 3-, 4-,        5-, 6-, 7 or 8-quinolyl-(C₁-C₄)-alkyl radical, where the        (C₁-C₄)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl radical may be        unsubstituted or mono- to hexasubstituted by identical or        different substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, preferably methyl, particularly preferably        2-methyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        N,N-di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,        (C6-C14)-aryl-(C1-C6)-alkyoxy [sic], preferably benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by halogen,        preferably trifluoromethyl, (C₆-C₁₄)-aryl and        (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl, except for (C₁-C₆)-alkyl-,        halogen-, nitro-, amino- and (C1-C6)-alkylamino-substituted or        unsubstituted 2-, 3-, 4- and 8-quinolyl and 2-, 3- and        4-quinolylmethyl in which the ring carbon atoms of the        pyridylmethyl moiety are unsubstituted or substituted by        (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, amino and        (C₁-C₆)-alkoxycarbonylamino;    -   a 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl radical or 1-, 3-, 4-,        5-, 6-, 7- or 8-isoquinolyl-(C₁-C₄)-alkyl radical, where the        (C₁-C₄)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl radical may be        unsubstituted or mono- to hexasubstituted by identical or        different substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 6-, 8- or 9-[9H]-purinyl radical or 2-, 6-, 8- or        9-[9H]-purinyl-(C₁-C₄)-alkyl radical, where the (C₁-C₄)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2-, 6-, 8- or        9-[9H]-purinyl radical may be unsubstituted or mono- to        trisubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 6-, 7- or 8-[7H]-purinyl radical or 2-, 6-, 7- or        8-[7H]-purinyl-(C₁-C₄)-alkyl radical, where the (C₁-C₄)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2-, 6-, 7- or        8-[7H]-purinyl radical may be unsubstituted or mono- to        trisubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl radical or 1-,        2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl-(C₁-C₄)-alkyl radical,        where the (C₁-C6)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl radical may be        unsubstituted or mono- to octasubstituted by identical or        different substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl radical        or 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- or        10-phenanthridinyl-(C₁-C₆)-alkyl radical, where the        (C₁-C₆)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen and oxo        (═O) and the 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or        10-phenanthridinyl radical may be unsubstituted or mono- to        octasubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen, nitro, amino,        mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl-(C₁-C₆)-alkoxy, preferably        benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 3-, 4-, 5, -[sic] or 6-pyridyl radical where the 2-, 3-,        4-, 5, -[sic] or 6-pyridyl radical may be unsubstituted or mono-        to tetrasubstituted by identical or different substituents from        the group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl, with the proviso        that Z₁, Z₂, R₂, R₃ and R₄ have the meaning given above or        below, without any limitations, and R represents        (C₂-C₆)-alkenyl, preferably allyl, (C₂-C₆)-alkynyl, preferably        ethynyl or propargyl, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, or        straight-chain or branched cyano-(C₁-C₆)-alkyl, preferably        cyanomethyl, or with the proviso that Z₂, R, R₂, R₃ and R₄ have        the meanings described above or below, without any limitations,        and Z₁ denotes geminally attached hydrogen and hydroxyl;    -   a 2-, 3-, 4-, 5, -[sic] or 6-pyridyl-(C₁-C₆)-alkyl radical,        where the (C₁-C₆)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        2-, 3-, 4-, 5, -[sic] or 6-pyridyl radical may be unsubstituted        or mono- to tetrasubstituted by identical or different        substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 3-, 4, -[sic] or 5-thienyl radical or 2-, 3-, 4, -[sic] or        5-thienyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl radical        may be unsubstituted or mono- or polysubstituted by identical or        different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2-, 3-, 4, -[sic] or        5-thienyl radical may be unsubstituted or mono- to        trisubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 4-, or 5-thiazolyl radical or 2-, 4-, or        5-thiazolyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2-, 4-, or        5-thiazolyl radical may be unsubstituted or mono- or        disubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 3-, 4-, or 5-isothiazolyl radical or 3-, 4- or        5-isothiazolyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 3-, 4- or        5-isothiazolyl radical may be unsubstituted or mono- or        disubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 4-, 5-, 6- or 7-benzothiazolyl radical or 2-, 4-, 5-, 6-        or 7-benzothiazolyl-(C₁-C₆)-alkyl radical, where the        (C₁-C₆)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        2-, 4-, 5-, 6- or 7-benzothiazolyl radical may be unsubstituted        or mono- to tetrasubstituted by identical or different        substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 2-, 4- or 5-imidazolyl radical or 1-, 2-, 4- or        5-imidazolyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 1-, 2-, 4- or        5-imidazolyl radical may be unsubstituted or mono- to        trisubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 3-, 4- or 5-pyrazolyl radical or 1-, 3-, 4- or        5-pyrazolyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 1-, 3-, 4- or        5-pyrazolyl radical may be unsubstituted or mono- to        trisubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 2, -[sic] 3, -[sic]-4, -[sic] or 5-pyrrolyl radical or 1-,        2, -[sic] 3, -[sic]-4, -[sic] or 5-pyrrolyl-(C₁-C₆)-alkyl        radical, where the (C₁-C₆)-alkyl radical may be unsubstituted or        mono- or polysubstituted by identical or different substituents        from the group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O)        and the 1-, 2, -[sic] 3, -[sic] 4, -[sic] or 5-pyrrolyl radical        may be unsubstituted or mono- to tetrasubstituted by identical        or different substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 3-, or 5-[1.2.4]-triazolyl radical or 1-, 3- or        5-[1.2.4]-triazolyl-(C₁-C₆)-alkyl radical, where the        (C₁-C₆)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen and oxo        (═O) and the 1-, 3- or 5-[1.2.4]-triazolyl radical may be        unsubstituted or mono- or disubstituted by identical or        different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 4- or 5-[1.2.3]-triazolyl radical or 1-, 4- or        5-[1.2.3]-triazolyl-(C₁-C₆)-alkyl radical, where the        (C₁-C₆)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        1-, 4- or 5-[1.2.3]-triazolyl radical may be unsubstituted or        mono- or disubstituted by identical or different substituents        from the group consisting of hydrogen, (C₁-C₆)-alkyl, halogen,        nitro, amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino,        hydroxyl, (C₁-C₆)-alkoxy, benzyloxy, carboxyl,        (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1- or 5-[1H]-tetrazolyl radical or 1- or        5-[1H]-tetrazolyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 1- or        5-[1H]-tetrazolyl radical may be unsubstituted or substituted by        hydrogen, (C₁-C₆)-alkyl, halogen, nitro, amino,        mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2- or 5-[2H]-tetrazolyl radical or 2- or        5-[2H]-tetrazolyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2- or        5-[2H]-tetrazolyl radical may be unsubstituted or substituted by        hydrogen, (C₁-C₆)-alkyl, halogen, nitro, amino,        mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 4- or 6-[1.3.5]-triazinyl radical or 2-, 4- or        6-[1.3.5]-triazinyl-(C₁-C₆)-alkyl radical, where the        (C₁-C₆)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen and oxo        (═O) and the 2-, 4- or 6-[1.3.5]-triazinyl radical may be        unsubstituted or mono- or disubstituted by identical or        different substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 2-, 4- or 5-oxazolyl radical or 2-, 4- or        5-oxazolyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 2-, 4-, or        5-oxazolyl radical may be unsubstituted or mono- or        disubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 3-, 4- or 5-isoxazolyl radical or 3-, 4- or        5-isoxazolyl-(C₁-C₆)-alkyl radical, where the (C₁-C₆)-alkyl        radical may be unsubstituted or mono- or polysubstituted by        identical or different substituents from the group consisting of        (C₁-C₆)-alkyl, halogen and oxo (═O) and the 3-, 4- or        5-isoxazolyl radical may be unsubstituted or mono- or        disubstituted by identical or different substituents from the        group consisting of hydrogen, (C₁-C₆)-alkyl, halogen, nitro,        amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxyl,        (C₁-C₆)-alkoxy, benzyloxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,        (C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkyl which is mono- or        polysubstituted by fluorine, preferably trifluoromethyl,        (C₆-C₁₀)-aryl and (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl;    -   a 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl radical or 1-, 2-, 3-, 4-,        5-, 6- or 7-indolyl-(C₁-C₆)-alkyl radical, where the        (C₁-C₆)-alkyl radical may be unsubstituted or mono- or        polysubstituted by identical or different substituents from the        group consisting of (C₁-C₆)-alkyl, halogen and oxo (═O) and the        1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl radical may be unsubstituted        or mono- to hexasubstituted by identical or different        substituents from the group consisting of hydrogen,        (C₁-C₆)-alkyl, halogen, nitro, amino, mono-(C₁-C₆)-alkylamino,        di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, benzyloxy,        carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino or        (C₁-C₆)-alkyl which is mono- or polysubstituted by fluorine,        preferably trifluoromethyl, (C₆-C₁₀)-aryl and        (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl, and also the isomers, in particular        tautomers, diastereomers and enantiomers, and the        pharmaceutically acceptable salts, in particular acid addition        salts, thereof [lacuna].

According to a further embodiment, indole derivatives of the generalformula (1) are provided which are characterized in that R, R2, R3, R4,Z1 and Z2 have the meanings described above and R₁ represents quinolylwhich is mono- or polysubstituted by straight-chain or branched(C₁-C₆-alkyl) or (C₁-C₆)-alkoxy.

According to a further embodiment, indole derivatives of the generalformula (1) are provided which are characterized in that R, R2, R3, R4,Z1 and Z2 have the meanings described above and R₁ represents2-methyl-6-quinolyl.

According to a further embodiment, indole derivatives of the generalformula (1) are provided which are characterized in that R, R2, R3, R4Z1 and Z2 have the meanings described above and R₁ denotes(2-methyl)-6-quinolyl, R₂ denotes 4-chlorobenzyl, R₃ and R₄ each denotehydrogen and Z₁ and Z₂ each denote oxygen.

According to a further aspect of the invention, a process for preparingindole derivatives of the general formula (1) according to any of claims1 to 5 is [lacuna] which is characterized in that an indole precursor ofthe general formula (2)

in which R2, R3 and R4 have the meanings mentioned above is reacted witha compound of the general formula (3)

in which Z1 and Z2 have the meaning mentioned above and Y1 and Y2independently of one another represent a suitable leaving group, such ashalogen, (C1-C6)-alkoxy, —O-tosyl, —O-mesyl or —N1-imidazole, and thenwith an amine of the general formula (4) or (5)

in which R and R1 have the meanings mentioned above, giving the desiredindole derivative of the general formula (1) (with amine 4) or thecompound of the general formula (6) (with amine 5)

in which R1, R2, R3, R4, Z1 and Z2 have the meanings mentioned above,using, if appropriate, diluents and auxiliaries, where the compound ofthe general formula (6) may subsequently be reacted with a compound ofthe general formula (7)R—Y3  (7)in which R has the meaning mentioned above and Y3 represents a suitableelectrophilic leaving group, such as halogen, (C1-C6)-alkoxy, —O-tosyl,—O-mesyl or —N1-imidazole, giving the desired compound (1), where R doesnot denote hydrogen, using, if appropriate, diluents and auxiliaries.Synthesis Routes:

The compounds of the general formula 1 can be obtained according toScheme 1 below:

Furthermore, the compounds of the general formula 1 can also be obtainedby the synthesis route of Scheme 2:

The compounds of the general formula 1 in which R=methyl, benzyl,propargyl or cyanomethyl and R₁, R₂, R₃ and R₄ have the meanings givenfor the general formula 1 can also be prepared according to thesynthesis route of Scheme 3:

The starting materials (2), (3) and (4) are either commerciallyavailable or can be prepared by procedures known per se. The startingmaterials (2), (3) and (4) are useful intermediates for preparing theindole derivatives of the formula (1) according to the invention.

For the preparation of starting materials and target compounds,reference may be made, for example, to the following standard works oforganic synthesis, the content of which is hereby explicitly includedinto the disclosure of the present application:

-   1) Houben-Weyl, Volume E 7a (part 1) pp. 290492, pp. 571-740    -   Houben-Weyl, Volume E 7a (part 2) pp. 119-156, pp. 205-686, pp.        157-204-   2) Monograph “Heterocyclic Compounds” (Elderfield),    -   Volume 1, pp. 119-207, pp. 397-616    -   Volume 3, pp. 1-274    -   Volume 6, pp. 101-135, pp. 234-323-   3) Monograph “Comprehensive Organic Chemistry” (S. D. Barton, W. D.    Ollis)    -   Volume 4, pp. 155-204, pp. 205-232, pp. 493-564

The solvents and auxiliaries to be used, if appropriate, and thereaction parameters to be used, such as reaction temperature andreaction time, are known to the person skilled in the art owing to hisexpert knowledge.

The indole derivatives of the general formula (1) according to theinvention are suitable as medicaments, in particular as antitumoragents, for treating mammals, in particular man, but also domesticanimals such as horses, cattle, dogs, cats, hares, sheep, poultry andthe like.

According to a further aspect of the invention, a method for controllingtumors in mammals, in particular man, is provided which is characterizedin that at least one indole derivative of the general formula (1) isadministered to a mammal in an amount effective for the treatment of thetumor. The therapeutically effective dose of the indole derivativeaccording to the invention in question which is to be administered forthe treatment depends inter alia on the nature and the stage of theoncosis, the age and the sex of the patient, the type of administrationand the duration of the treatment. Administration can take place orally,rectally, buccally (for example sublingually), parenterally (for examplesubcutaneously, intramuscularly, intradermally or intravenously),topically or transdermally.

According to a further aspect of the invention, medicaments for thetreatment of tumors are provided which are characterized in that theycomprise, as active ingredient, at least one indole derivative accordingto any of claims 1 to 5 or a pharmaceutically acceptable salt thereof,if appropriate together with customary pharmaceutically acceptableauxiliaries, additives and carriers. These can be solid, semisolid,liquid or aerosol preparations. Suitable solid preparations are, forexample, capsules, powders, granules, tablets. Suitable semisolidpreparations are, for example, ointments, creams, gels, pastes,suspensions, oil-in-water and water-in-oil emulsions. Suitable liquidpreparations are, for example, sterile aqueous preparations forparenteral administration which are isotonic with the blood of thepatient.

The invention is to be illustrated in more detail by the example below,without being restricted to the example.

WORKING EXAMPLES Example 1 Reaction According to Scheme 1, 1. StepPreparation of 1-(4-chlorobenzyl)indole

A solution of 5.86 g (0.05 mol) of indole in 25 ml of DMSO is added to amixture of 1.32 g of sodium hydroxide (0.055 mol, suspension in mineraloil) in 50 ml of dimethyl sulfoxide. The mixture is heated at 60° C. for1.3 hours and then allowed to cool, and 17.7 g (0.11 mol) of4-chlorobenzyl chloride are added dropwise. The solution is heated at60° C., allowed to stand overnight and then poured with stirring into200 ml of water. The mixture is extracted repeatedly with a total of 75ml of CH₂Cl₂, the organic phase is dried with anhydrous sodium sulfateand filtered and the filtrate is concentrated under reduced pressure.

Yield: 11.5 g (95% of theory)

Example 2 Reaction According to the 2. Step of Scheme 1 Preparation ofN-(2-methyl-6-quinolyl)-[1-(4-chlorobenzyl)indole-3-yl]glyoxylamide(D-69429)

At 0° C. and under nitrogen, a solution of 10.2 g (42.2 mmol) of1-(4-chlorobenzyl)indole in 50 ml of ether is added dropwise to asolution of 5.50 ml of oxalyl chloride in 50 ml of ether. The mixture isheated at reflux for 2 hours and the solvent is then evaporated. 100 mlof tetrahydrofuran were then added to the residue and the solution wascooled to −4° C. and treated dropwise with a solution of 15.66 g (99.0mmol) of 6-amino-2-methylquinoline in 350 ml of THF. The mixture isheated at reflux for 4 hours and allowed to stand at room temperatureovernight. The 6-amino-2-methylquinoline hydrochloride is filtered offwith suction, the precipitate is washed with THF, the filtrate isconcentrated under reduced pressure and the residue is recrystallizedfrom methyl ethyl ketone/methylene chloride.

Yield: 14.8 g (77.3% of theory)

Melting point: 182-185° C.

Synthesis of the Hydrochloride:

To a mixture of 0.453 g (1 mMol)N-(2-Methyl-6-quinolyl)-[1-(4-chlorobenzyl)-indol-3-yl]-glyoxylic acidamide in 20 ml hot ethanol is added under stirring the equivalentquantity of isopropanolic hydrochloric acid. The suspension is heated to70-80° C. and the formed solution is evaporated to dryness under reducedpressure. The evaporating process is repeated several times with tolueneto give the colorless and crystalline hydrochloride.

Yield: 0.49 g (100% of the theoretical)

Mp.: 196° C.

Synthesis of the Methansulfonate:

A mixture of 0.453 g (1 mMol)N-(2-Methyl-6-quinolyl)-[1-(4-chlorobenzyl)-indol-3-yl]-glyoxylic acidamide and 0.67 ml Methanesulfonic acid in 15 ml Dichloromethane isheated to 50° C. for 30 minutes. The so formed solution is concentratedund reduced pressure at 35° C. to dryness. The residue is evaporatedseveral times with methyl-tert.-butylether, dried in the vacuo at 35° C.to provide the methansulfonate as white crystals.

Yield: 0.46 g (84% of the theoretical)

Mp.: >230° C.

Example 3 Reaction According to Scheme 3 Preparation ofN-propargyl-N-(2-methyl-6-quinolyl)-[1-(4-chlorobenzyl)indol-3-yl]glyoxylamide

At room temperature and under nitrogen, a suspension of 2.32 g (5.13mmol) ofN-(2-methyl-6-quinolyl))-[1-(4-chlorobenzyl)indol-3-yl]glyoxylamide in20 ml of DMF is added to a suspension of 0.154 g of sodium hydride (5.13mmol, suspension in mineral oil) in 10 ml of DMF. This resulted instrong foaming, with the mixture turning yellow. A solution of 0.382 g(5.13 mmol) of propargyl chloride in 10 ml of DMF is added dropwise, andthe mixture is, under nitrogen gas, stirred at room temperature for 24hours and allowed to stand at room temperature for 4 days. Thedark-brown solution is then poured into 120 ml of ice water andextracted in portions with 250 ml of methylene chloride, and thecombined organic phases are dried using anhydrous sodium sulfate. Theextract is concentrated under reduced pressure and the residue ispurified using a silica gel column (silica gel 60, from Merck AG,Darmstadt, Germany) and the mobile phase methylene chloride/ethanol(97:3, v/v).

Yield: 1.98 g (78.6% of theory)

Mass spectrum: m/e=491.9 (M⁺)

Biological Tests

1. Antiproliferative Action in Various Tumor Cell Lines

In a proliferation test, the antiproliferative activity of the substanceD-69429 was examined using established tumor cell lines. In the testused, the cellular dehydrogenation activity is determined, which makesit possible to determine the vitality of the cell and, indirectly, thecell count. The cell lines used are the human cervical carcinoma cellline KB/HeLa (ATCC CCL17), the murine lymphocyte leukaemia L1210 (ATCCCCL-219), the human breast adenocarcinoma line MCF7 (ATCC HTB22) and theovary adenocarcinoma line SKOV-3 (ATCC HTB77). These are establishedcell lines which are very well characterized and were obtained from ATCCand cultured.

The results shown in Tab. 1 demonstrate the highly potentantiproliferative action of D69429 in the cell lines SKOV-3, L-1210 andHeLa/KB. Owing to the particularly slow growth of the MCF7 line, theeffect of D-69429 in the test period of 48 h is only small (18%inhibition at 3.16 μg/ml; thus stated as >3.16).

2. Method

XTT Test for Cellular Dehydrogenase Activity

The adherently growing tumor cell lines HeLa/KB, SKOV-3 and MCF7 and theL1210 leukaemia line, which grows in suspension, were cultivated understandard conditions in an incubator with gas inlet at 37° C., 5% CO₂ and95% atmospheric humidity. On Test Day 1, the adherent cells are detachedusing trypsin/EDTA and pelleted by centrifugation. The cell pellet isthen resuspended in the RPMI culture medium at the appropriate cellcount and transferred to a 96-well microtiter plate.

The plates are then cultivated overnight in the incubator with gasinlet. The test substances are made up as stock solutions in DMSO and,on Test Day 2, diluted with culture medium to the correspondingconcentrations. The substances in the culture medium are then added tothe cells and incubated in the incubator with gas inlet for 45 h. Cellswhich have not been treated with test substance serve as control.

For the XTT assay, 1 mg/ml of XTT (sodium3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonicacid) is dissolved in RPMI-1640 medium without Phenol Red. Additionally,a 0.383 mg/ml solution of PMS (N-methyldibenzopyrazine methyl sulfate)in phosphate-buffered saline (PBS) is prepared. On Test Day 4, 75μl/well of the XTT-PMS mixture are pipetted onto the cell plates, whichby now have been incubated with the test substances for 45 h. To thisend, the XTT solution is mixed with the PMS solution in a ratio of 50:1(v/v) shortly before use. The cell plates are then incubated in theincubator with gas inlet for a further 3 h, and the optical density(OD_(490 nm)) is determined in a photometer.

Using the OD_(490 nm) obtained, the inhibition in percent relative tothe control is calculated. The antiproliferative activity is estimatedusing regression analysis.

Example I

Tablet Containing 50 mg of Active Compound

Composition:

(1) Active compound 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg(4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg Total:215.0 mgPreparation:

(1), (2) and (3) are mixed and granulated with an aqueous solution of(4). The dried granules are admixed with (5). This mixture is tabletted.

Example II

Capsule Containing 50 mg of Active Compound

Composition:

(1) Active compound 50.0 mg (2) Maize starch, dried 58.0 mg (3) Lactosepowder 50.0 mg (4) Magnesium stearate 2.0 mg Total: 160.0 mgPreparation:

(1) is ground with (3): This ground material is added with vigorousmixing to the mixture of (2) and (4). This powder mixture is, on acapsule filling machine, filled into hard gelatine capsules size 3.

1. Indole compounds of the general Formula 1

in which R denotes hydrogen; straight-chain or branched (C₁-C₆)-alkyl;(C₁-C₆)-alkyl which is mono- or polysubstituted by aryl, where the arylradical [lacuna] unsubstituted or mono- to penta-[lacuna] by identicalor different substituents from the group consisting of halogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, carboxyl, (C₁-C₆)-alkoxy-carbonyl,straight-chain or branched (C₁-C₆)-alkyl, which is substituted by one ormore fluorine atoms, hydroxyl, straight-chain or branched(C₁-C₆)-alkoxy; benzyloxy or aryl-(C₁-C₆)-alkyl, where the aryl radicalmay be unsubstituted or mono- or pentasubstituted by identical ordifferent substituents from the group consisting of (C₁-C₆)-alkyl,halogen and straight-chain or branched (C₁-C₆)-alkyl which issubstituted by one or more fluorine atoms; straight-chain or branched(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, substituted or unsubstitutedaryl-(C₁-C₆)-alkyloxycarbonyl, straight-chain or branched(C₁-C₆)-alkyloxycarbonyl, straight-chain or branched(C₁-C₆)-alkylcarbonyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, orstraight-chain or branched cyano-(C₁-C₆)-alkyl; R₁ denotes apyrido[2,3-b]-pyrazinyl group; R₂ denotes hydrogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl which is mono- or polysubstituted by halogen,(C₁-C₆)-alkyl which is mono- or polysubstituted by phenyl, where thephenyl radical may be unsubstituted or mono- to pentasubstituted byidentical or different substituents from the group consisting ofhalogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, carboxyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkyl which is mono- or polysubstitutedby halogen, hydroxyl, (C₁-C₆)-alkoxy, phenyl-(C₁-C₆)-alkoxy, nitro,amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino,mono-(C₃-₆)-cycloalkylamino, di-(C₃₋₆)-cycloalkylamino,(C₁-C₆)-acylamino, phenyl-(C₁-C₆)-alkylamino, arylcarbonylamino,heteroarylcarbonylamino, (C₁-C₆)-alkylsulfonamido, arylsulfonamido,maleinimido, succinimido, phthalimido, benzyloxycarbonylamino (Z-amino),tert-butoxycarbonylamino (BOC-amino), 9-fluorenylmethoxycarbonylamino(Fmoc-amino), triphenylmethylamino (Tr-amino),2-(4′-pyridyl)-ethoxycarbonylamino (Pyoc-amino),diphenylmethylsilylamino (DPMS-amino), —NH—CH₂—COOH; —NH—CH(CH₃)—COOH;(CH₃)₂CH—CH₂—CH₂—CH(NH—)—COOH; H₃C—CH₂—CH(CH₃)—CH(NH—)—COOH;HOH₂C—CH(NH—)—COOH; phenyl-CH₂—CH(NH—)—COOH;(4-imidazolyl)-CH₂—CH(NH—)—COOH; HN═C(NH₂)—NH—(CH₂)₃—CH(NH—)—COOH;H₂N—(CH₂)₄—CH(NH—)—COOH; H₂N—CO—CH₂—CH(NH—)—COOH; orHOOC—(CH₂)₂—CH(NH—)—COOH; R₃ and R₄ may be attached to the indole carbonatoms C-2, C-4, C-5, C-6 or C-7 and independently of one another denotehydrogen, hydroxyl, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxy, halogen, aryl-(C₁-C₄)-alkoxy,nitro, amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,(C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)-alkoxycarbonylamino-(C₁-C₆)-alkyl,cyano, straight-chain or branched cyano-(C₁-C₆)-alkyl, carboxyl,(C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkyl which is substituted by one ormore fluorine atoms, carboxy-(C₁-C₆)-alkyl or(C₁-C₆)-alkoxycarbonyl-(C₁-C₆)-alkyl; Z₁ denotes oxygen or sulfur; Z₂denotes oxygen or sulfur, their tautomers, stereoisomers, including thediastereomers and enantiomers, and the physiologically acceptable saltsthereof.
 2. Indole compounds of the general formula (1) according toclaim 1, characterized in that R, R₂, R₃, R₄, Z₁ and Z₂ have themeanings given above and R₁ depicts a pyrido[2,3-b]-pyranzinyl group.